Journal
EPILEPSIA
Volume 51, Issue 9, Pages 1650-1658Publisher
WILEY
DOI: 10.1111/j.1528-1167.2010.02640.x
Keywords
GEFS; Dravet syndrome; Genetics; Knock-in mice; Knockout mice
Categories
Funding
- NIH [NS065187, NS046484, NS066155, NS048336]
- McKnight Foundation [34653]
- Epilepsy Foundation
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS066155, R01NS046484, R01NS048336, R01NS065187] Funding Source: NIH RePORTER
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Mutations in a number of genes encoding voltage-gated sodium channels cause a variety of epilepsy syndromes in humans, including genetic (generalized) epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS, severe myoclonic epilepsy of infancy). Most of these mutations are in the SCNIA gene, and all are dominantly inherited. Most of the mutations that cause DS result in loss of function, whereas all of the known mutations that cause GEFS+ are missense, presumably altering channel activity. Family members with the same GEFS+ mutation often display a wide range of seizure types and severities, and at least part of this variability likely results from variation in other genes. Many different biophysical effects of SCNIA-GEFS+ mutations have been observed in heterologous expression systems, consistent with both gain and loss of channel activity. However, results from mouse models suggest that the primary effect of both GEFS+ and DS mutations is to decrease the activity of GABAergic inhibitory neurons. Decreased activity of the inhibitory circuitry is thus likely to be a major factor contributing to seizure generation in patients with GEFS+ and DS, and may be a general consequence of SCNIA mutations.
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